Highly affine cosmetic agent

ABSTRACT

The invention relates to a cosmetic agent which is made essentially of a peptide linker and at least one cosmetic active ingredient which is covalently connected thereto.

The present invention relates to cosmetic agents comprising twocomponents covalently linked to each other and having functions thatdiffer from one another, the first component being a peptidic linkermolecule with high affinity or binding specificity forkeratin-containing material and the second component being at least onecosmetic agent consisting of at least one cosmetically active compoundknown per se or a cosmetic effector molecule for the cosmetic treatmentof keratin-containing material.

The combination of the invention finds general use in the cosmetictreatment of parts of the human or animal body that contain keratin andparticularly as a hair-treating agent.

The targeted and in terms of quantity and method optimum use of cosmeticproducts is based on the idea of being able to apply the agents ormaterials in question in as efficient a manner as possible to thedesired parts of the body and to exclude as much as possible other areasof the body.

To achieve this goal, three methods are available in principle.According to one method, the cosmetic agent exhibiting the desiredaction can be applied to the desired body site locally by means ofappropriate mechanical aids, while at the same time covering the bodyareas with which the cosmetic agent in question is not to come incontact. This method, however, has the drawback that it allows one toreach only the directly accessible parts of the body, that contact withundesirable body sites can practically be difficult to avoid and thatthe handling of the method is awkward.

According to the second method, it is possible, based on certainchemical and biochemical/physiological properties, to select cosmeticagents that preferentially bind or adhere to certain structures (forexample skin, hair, nails). The drawback of these methods is, inparticular, that the use of these substances is highly restricted bytheir chemical nature so that the desired site-specific action of thecosmetic agent in question often does not occur in the hoped-for mannerand that the material is not suited for cosmetic use.

As a third possibility, it has recently been proposed to use variousantibodies with different specificity for cosmetic agents as vehiclesfor a targeted application of cosmetic agents. In this manner, bycoupling with antibodies, the cosmetic agents are transported to thedesired sites.

Such methods have, in particular, the drawback that the preparation ofthe antibodies is very expensive and that antibodies are relativelylarge, complicated and biologically active protein units the use ofwhich, as is known, is not without problems from both a biochemical anda physiological standpoint.

The object of the present invention is to provide cosmetic agents andnovel methods for cosmetic treatment that eliminate the drawbacks of theprior art.

According to claim 1, this objective is reached by providing ahigh-affinity cosmetic agent comprising two components that arecovalently linked to each other and have functions that differ from oneanother, the first component being a peptidic linker molecule with highaffinity or binding specificity for keratin-containing material, and thesecond component being at least one cosmetic agent consisting of atleast one known organic cosmetically active compound or an organiccosmetically active effector molecule.

Surprisingly, we have now found that peptides with a chain length ofbetween 2 and 30 amino acids, preferably between 6 and 15 amino acidsand particularly between 6 and 12 amino acids, on the one hand, can bindspecifically to keratin-containing material, particularly hair, and, onthe other, can be linked with cosmetically active compounds in a mannersuch that with the said peptidic linker molecule the cosmetically activecompound in question can be applied in advantageous manner to akeratin-containing material (particularly hair)

In this manner a cosmetic agent is obtained which consists of twocomponents covalently linked to each other, namely a peptidic linkermolecule with binding specificity for keratin or keratin-containingmaterial, and at least one cosmetic agent bound thereto. The peptidiclinker molecule acts as a binding agent and vehicle for the cosmeticallyactive compound, it being possible for several cosmetically activecompounds to be linked to the same peptidic linker. A cosmetic agentwith high affinity for the keratin-containing material, particularly foranimal and human hair, is obtained in this manner.

Another object of the present invention is the use of the cosmetic agentin question for cosmetic treatment of keratin-containing material andthe use of the peptidic linker molecule in question and of the effectormolecules for the preparation of a cosmetic agent with high affinity orbinding specificity for keratin or keratin-containing material.

The cosmetic agent according to the present invention has numerousadvantages. Particularly noteworthy among these is the targeted use ofcosmetic agents (dyes, cosmetic care agents, conditioners) so that theseagents can exert their action essentially only at certain desired sitesof the body, particularly on hair. Moreover, in this manner it ispossible to achieve a stronger and longer-lasting hold of the cosmeticagent at the application site, particularly hair, so that, dependingalso on the binding strength of the peptidic linker molecule, acontrollable or controlled retention time or intensity of the cosmeticagent, for example a dye, can be attained. A lower quantitativeconsumption of the cosmetic agent in question can be pointed out as anadditional advantage.

Moreover, with the cosmetic agent of the present invention, severaladvantageous properties can be combined in one and the same product. Forexample, an effector molecule with hair-care action can, via thepeptidic linker, be linked with a hair dye molecule giving rise to aproduct that at the same time is a hair-care product and a haircolorant.

Also, the peptidic linker itself can have cosmetic care properties sothat with even just a single binding, for example, of a color-producingeffector molecule to a peptidic linker, it is possible to obtainproducts that at same time are cosmetic care-imparting products andcolorants. Thus, the cosmetic agent of the invention can exhibit atleast two different cosmetic actions.

Another advantage of the cosmetic agent of the invention is its veryhigh variability which can also be controllable. For example, differentpeptidic linkers with different binding strengths for keratin-containingmaterial can be linked with entirely different effector molecules, forexample a surface-active substance and a hair dye. In this case, acosmetic agent is provided in which the effector molecules, through thedifferent binding properties of “their” peptidic linkers, can provide anindividual retention time or individual properties at the site ofapplication.

Furthermore, hair damaged by mechanical action (for example combing orrubbing), chemical action (for example dyeing, bleaching, waving,defrizzing) or physical action (UV radiation, weathering effects) can,compared to healthy hair, show different binding strengths and bindingsites for the peptidic linker. In such cases, a cosmetic agent of theinvention can bind preferentially to damaged areas of the hair, forexample hair tips damaged by splicing, because the peptidic linkermolecule binds preferentially and unusually strongly with acosmetic-care effector molecule and/or a coloring effector moleculeand/or an effector molecule acting as a UV filter.

From this, a person skilled in the art can clearly see the possibilitiesoffered by the present invention of providing numerous cosmetic agentswith advantageously combined properties.

By “keratin-containing material” are meant for purposes of the presentinvention the skin and skin appendages, for example scalp hair,eyebrows, eyelashes, toenails and fingernails of the animal and humanbody.

By “peptidic linker molecule” are meant for purposes of the presentinvention polymers the monomers of which are amino acids connected toeach other by the usual acid amide bonds. Said polymers can be ofsynthetic (prepared by total industrial synthesis), semisynthetic(obtained by partial synthesis and from natural sources) or naturalorigin, methods of preparation involving genetic engineering (forexample the known methods of DNA recombination, phage-peptide librariesor phage display) being included. Suitable amino acids are both theL-and the D-amino acids as well as the amino acids modified by, forexample, glycosylation (by methods that in themselves are known).

By “cosmetic agents” or “cosmetically active compounds” or “cosmeticeffector molecules” are meant compounds, substances or molecules whichare known to exert a cosmetic action on the surface of the animal orhuman body, particularly those with dyeing or coloring, cosmeticcare-imparting, conditioning, protective, hardening, softening,repairing and/or reconstituting properties. In the following, the term“effector molecule” is used as a synonym for “cosmetic agent” or“cosmetically active agent”.

Thus, the present invention includes the use of a peptidic linkermolecule and at least one organic cosmetically active effector moleculewith dyeing or coloring, cosmetic care-imparting, conditioning,protective, hardening, softening, repairing and/or reconstitutingproperty for preparing a cosmetic agent.

The coupling of a peptidic linker molecule with an effector molecule canbe achieved by known chemical methods.

Preferred peptidic linker molecules are glycine or glycine derivativeswhich for binding to effector molecules contain appropriate heteroatomsor heteroatom groupings. Suitable glycine derivatives are thealpha-amino acids with at least three carbon atoms, the suitableheteroatoms or heteroatom groups, for example an amino, hydroxyl,sulfonyl or carboxyl group, preferably being attached to the terminalcarbon atom.

Suitable effector molecules are preferably dyes or dye precursorscontaining a reactive group capable of forming a covalent bond with theheteroatoms or heteroatom groups.

Suitable reactive groups are, for example, the triazinyl,sulfatoethoxysulfonyl or vinylsulfonyl groups. It is also possible,however, to use as the reactive groups halopyrimidine, chloracetamide,carbamate, epoxide or methylol groups.

Suitable dye precursors are, for example, halonitroaromatic compoundssuch as 2,4-dinitrofluorobenzene, 2,6-dinitrofluorobenzene or4-fluoro-3-nitroaniline.

The coupling reaction of an effector molecule can take place, forexample, according to the following scheme. In this case which is usedas an example, the effector molecule is a dye or dye precursor.

According to the following reaction scheme, glycine derivatives offormula I can be condensed with dyes or dye precursors R_(F)-Ycontaining an appropriate reactive group to give dyes of formula II;

wherein R_(F) denotes a dye or dye precursor, R_(S) denotes a hydrogenatom or a t-butoxycarbonyl (Boc) group, L denotes an alkylene group orphenylene group and X denotes an amino, hydroxyl or sulfonyl group, andY is selected from among a halogen atom (F, Cl, Br) or one of thefollowing atomic groupings:

wherein R_(s), R_(y) and R_(z) independently of each other denote F, Cl,Br or an NR1R2 group, an OR1 or an SR1 group, provided that R1 and R2independently of each other stand for a hydrogen atom, a straight-chainor branched C₁-C₆-alkyl group, an aromatic or heteroaromatic ring with5-6 ring atoms or a totally or partly saturated ring compound with 5 to7 ring atoms.

Suitable derivatives of the amino acids of formula I are preferablycompounds containing a free amino, hydroxyl or sulfonyl group, forexample the derivatives of 3-aminoalanine, ornithine, lysine, serine,threonine, cysteine and homocysteine.

The finding and selecting of a peptidic linker molecule with bindingspecificity for keratin-containing material suitable for the purpose ofthe present invention can be accomplished by known methods and istrivial for a person skilled in the art.

The peptidic linkers and masked amino acids suitable for the presentinvention can be prepared by known methods or obtained commercially, forexample from ORPEGEN Pharma, Heidelberg. For example, a peptide of thedesired chain length of, for example, 10 amino acids can be synthesizedby routine methods, for example by the generally known Merrifieldtechnique.

The choice of amino acids that are suitable for the synthesis of thepeptide preferably depends on their charges or on the arrangement ofcharged side groups and/or of amino acid side groups capable of forminghydrogen bonds. Among such amino acids can be mentioned, for example,glutamic acid, aspartic acid, arginine, histidine, tyrosine, threonineand lysine.

Moreover, suitable peptides can be identified by the screening of phagepeptide libraries (also known as “phage display”, for example accordingto Devlin, J. J. et al., Science 249, 404-406, 1990) and by possiblefurther optimization thereof by the “cosmix-plexing” method according toWO 98/33901.

The peptides that are suitable as peptidic linker molecules and havesufficiently high binding affinity for keratin-containing material canbe selected by known methods, for example, by bringing akeratin-containing material, preferably hair, in contact with at leastone linker-effector combination according to the present invention. Thiscan be accomplished, for example, by immersing a hair sample into anaqueous solution at room temperature (20 to 22° C.) at a pH in the rangefrom 5 to 6, the solution containing a combination of a peptidic linkerand a colored effector molecule (for example,6-[(4-amino-2-nitrophenyl)amino]-(2S)-2{[(1,1-dimethylmethoxy)carbonyl]amino}hexanoicacid). After an exposure time of about 2 to 10 minutes, the binding ofthe effector molecule to the hair can then be determined by wash-outtests with a common hair-washing agent (shampoo).

The binding affinity for the keratin-containing material of the peptidiclinker molecules that are suitable for the invention is not critical.According to the invention, appropriate are peptidic linkers showingspecific binding to keratin-containing material in aqueous solution at apH in the range from 4.0 to 8.5, preferably from 5.0 to 6.0, and, incomparison with a sample with, for example, a simple hair dye withoutpeptidic linker, withstands at least four common hair washings with aconventional shampoo without an appreciable loss in efficacy.

The higher the affinity of the peptidic linker the stronger is theadherence of the cosmetic agent in question to the desired site ofapplication.

By selecting the peptidic linker according to its affinity for keratinor keratin-containing material, the cosmetic agent in question willadhere to the site of application more or less strongly so that with thepresent invention the effector molecules in question can be bonded withvarying strength, fastness or permanence. It is thus possible to preparecosmetic agents which in terms of retention time are quite differentlyadapted to the individual requirements.

As already stated, the term effector molecule includes substances thatexert a cosmetic action on the surface of an animal or human body,particularly substances with dyeing or coloring, cosmetic care-imparing,conditioning, protective, hardening, softening, repairing and/orreconstituting properties.

Suitable effector molecules for the present invention are mainlycosmetic-care providing and/or conditioning and/or protective substanceswhich on the skin or body appendages, particularly hair, are known to beable to exert hardening, softening, repairing or reconstitutingactivity.

Included are, for example, combability improvers, for example cationicpolymers (for example Iniquat FC 370, Jaguar C-162, Polymer JR 125),protein hydrolyzates (for example from wheat), cationic surfactants (forexample cetyltrimethylammonium chloride, distearylammonium chloride),amidoamines, betaine esters, ester quats; luster-imparting agents, forexample silicon polyols and fatty alcohols, volume providers, forexample chitosan; humectants, for example lactates (for example cetyllactate), vitamins and provitamins or vitamin precursors, for examplepanthenol, and derivatives thereof, biotin, tocopherols, springinessimprovers, for example betaine and derivatives thereof, sugars, forexample polysaccharides, oligosaccharides, glucose, fructose or inuline;organic-chemical UV filters including all known UVA- UVB- and UVA/UVBfilter substances alone or combinations with one another, for examplethe derivatives of dibenzoylmethane (for example Parsol 1789 supplied byGivaudan/Roure, INCI name: butyl methoxydibenzoylmethane,benzylidenecamphor or derivatives thereof, particularlymethylbenzylidenecamphor (for example 3-benzylidenecamphor,3-(4-methylenebenzylidene)-d,l-camphor), and derivatives and esters ofcinnamic acid, particularly derivatives and esters of methoxycinnamicacid (for example octyl 4-methoxycinnamate or isopentyl4-methoxycinnamate), derivatives and esters of benzoic acid,particularly of 4-aminobenzoic acids, polyhydroxybenzoic acids (forexample methyl polyhydroxybenzoate or propyl polyhydroxybenzoate),esters of salicylic acid (for example 2-ethylhexyl salicylate or4-isopropylbenzyl salicylate), sulfonic acids, benzophenone andderivatives thereof, for example the sulfonic acid derivatives ofbenzophenone (for example, 2-hydroxy-4-methoxybenzophenone-5-sulfonicacid) as UVB/UVA filters or of benzimidazoles (for example2-phenylbenzimidazole-5-sulfonic acid) as well as the salts thereof,dibenzoylmethane or appropriate polypeptides, particularly oxygenradical scavengers, for example the known Mn, Fe or Zn superoxidedismutases, as well as the tocopherols and vitamins (for exampleascorbic acid).

The said cosmetic-care and/or conditioning and/or protective effectormolecules can be contained in the cosmetic agent of the invention in atotal amount from 0.001 to 30.0 wt. %, particularly from 0.01 to 25.0wt. %, more particularly from 0.1 to 15 wt. % and preferably from 0.5 to10.0 wt. %, based on the amount of cosmetic agent.

Also suitable are synthetic polymers, particularly acrylic polymers, forexample those from the group of crosspolymers of acrylates and alkylacrylates and/or acrylates and allyl ethers. Suitable for this purposeare, for example, the Pemulen®, Caopol® and Acrisint® (brands, forexample Perrnulen TR1 supplied by Goodrich (INCI name: Acrylates/C10-30Alkyl Acrylate Crosspolymer), Carbopol 1382, supplied by Goodrich (INCIname: Acrylates/C 10-30 Alkyl Acrylates Crosspolymer), Carbopol 2984supplied by Goodrich (INCI name: carbomer) or Carbopol Ultrez 10supplied by Goodrich (INCI name: carbomer); or Acrisint 400 supplied by3 V (INCI name: carbomer) which in the cosmetic agents of the inventioncan be present alone or in combination.

Such polymers can be present in the cosmetic agent in an amount from0.05 to 5.0 wt. %, particularly from 0.1 to 3.0 wt. % and moreparticularly from 0.1 to 1.0 wt. %, based on the total amount of thecosmetic agent.

Suitable dyes or coloring effector molecules are all known oxidative,non-oxidative, direct, natural, synthetic or semisynthetic dyes used forthe cosmetic dyeing or tinting of keratin-containing materials,particularly hair. Preferred according to the invention are direct dyes.Particularly well suited for this purpose are variously colored nitrodyes, azo dyes, quinone dyes, triphenylmethane dyes and acid and basicdyes.

Also to be mentioned among the suitable dyes are the reactive dyescontaining a triazinyl, sulfatoethylsulfonyl or vinylsulfonyl group, forexample Reactive Blue 2, Reactive Blue 19, Reactive Red 2, ReactiveOrange 16, Reactive Black 5 and Reactive Yellow 2.

Dye precursors can also be used. Suitable dye precursors are, forexample, the halonitrobenzene derivatives that can be made to react withcompounds having free amino or hydroxyl groups to give nitro dyes.Examples of such dye precursors are 4-fluoro-3-nitroaniline,5-fluoro-2-nitroaniline, 1-chloro-2,4-dinitrobenzene and1-fluoro-2,4-dinitrobenzene.

As blue nitro dyes can be mentioned, for example:

-   1,4-bis[(2′-hydroxyethyl)amino]-2-nitrobenzene,-   1,(2′-hydroxyethyl)amino-2-nitro-4-bis-(2″-hydroxyethyl)aminobenzene    (HC Blue No. 2),-   1-amino-3-methyl-4-(2′-hydroxyethyl)amino-6-nitrobenzene (HC Violet    No. 1),-   4,N-ethyl,N-(2″-hydroxyethyl)amino-1-(2″-hydroxyethyl)amino-2-nitrobenzene    hydrochloride (HC Blue No. 12),-   4-bis-(2′-hydroxyethyl)amino-1-(2″-methoxyethyl)amino-2-nitrobenzene    (HC Blue No. 11),-   1-[(2′,3′-dihydroxypropyl)amino]-2-nitro-4-[N-methyl-(2″-hydroxyethyl)amino]benzene    hydrochloride (HC Blue No. 10),-   1-[(2′,3′-dihydroxypropyl)amino]-2-nitro-4-[N-ethyl-(2″-hydroxyethyl)amino]benzene    hydrochloride (HC Blue No. 9),-   1-(3′-hydroxypropylamino)-2-nitro-4-bis-(2″-hydroxyethylamino)benzene    (HC Violet No. 2),-   4,N-methyl,N-(2′,3′-dihydroxypropyl)amino-1-methylamino-2-nitrobenzene    hydrochloride (HC Blue No. 6),-   4′-amino-2′-nitro-2″-carboxy-4″-dimethylaminodiphenylamine (HC Blue    No. 13),

As red nitro dyes can be mentioned, for example:

-   1-amino-4-(2′-hydroxyethyl)amino-2-nitrobenzene (HC Red No. 7),-   1-hydroxy-2-amino-4,6-dinitrobenzene,-   4-amino-2-nitrodiphenylamine (HC Red No. 1),-   1-amino-2-nitro-4-bis (2′-hydroxyethyl)aminobenzene hydrochloride    (HC Red No. 13),-   1-amino-2-nitro-4-(2′-hydroxyethyl)amino-5-chlorobenzene,-   1-(2′-hydroxyethyl)amino-2-nitroaminobenzene (HC Red No. 3),-   1-hydroxy-3-nitroaminobenzene,-   1-hydroxy-3-nitro-4-(2′-hydroxyethylamino)benzene,-   1-(2′-aminoethyl)amino-2-nitro-4-(2′-hydroxyethoxy)benzene (HC    Orange No. 2),-   3-nitro-4-(2′-hydroxyethyl)aminophenyl glyceryl ether (HC Orange No.    3),-   1-amino-5-chloro-4-(2′,3′dihydroxypropyl)amino-2-nitrobenzene (Red    No. 10),-   1,4-bis[(2′,3′-dihydroxypropyl)amino]-5-chloro-2-nitrobenzene (HC    Red No. 11),-   1-hydroxy-2-(2′-hydroxyethyl)amino-4,6-cinitrobenzene,-   3-nitro-4-ethylaminobenzoic acid,-   4-amino-2-nitrodiphenylamino-2-carboxylic acid,-   2-chloro-6-ethylamino-4-nitrophenol,-   2-amino-6-chloro-4-nitrophenol,-   1-hydroxy-3-nitro-4-(3′-hydroxypropylamino)benzene,-   2,5-diamino-6-nitropyridine,-   1,2,3,4-tetrahydro-6-nitroquinoxaline,-   7-amino-3,4-dihydro-4-nitro-2H-1,4-benzoxazine (HC Red 14).

As yellow nitro dyes can be mentioned, for example:

-   1-amino-2-(2′-hydroxyethyl)amino-5-nitrobenzene (HC Yellow No. 5),-   1-(2′-hydroxyethoxy)-2-(2″-hydroxyethyl)amino-5-nitrobenzene (HC    Yellow No. 4),-   1-(2′-hydroxyethyl)amino-2-nitrobenzene (HC Yellow No. 2),-   1-methoxy-2-(2′-hydroxyethyl)amino-5-nitrobenzene,-   1-hydroxy-2-amino-3-nitrobenzene,-   1-amino-2-methyl-6-nitrobenzene,-   1-(2′-hydroxyethyl)oxy-3-methylamino-4-nitrobenzene,-   1-methylamino-2-nitro-5-(2′,3′-dihydroxypropyl)oxybenzene,-   1-(2′-hydroxyethyl)amino-2-hydroxy-4-nitrobenzene (HC Yellow No.    11),-   1-methoxy-3-(2′-aminoethyl)amino-4-nitrobenzene hydrochloride (HC    Yellow No. 9),-   1-2′-ureidoethyl)amino-4-nitrobenzene,-   4-(2′,3′-dihydroxypropyl)amino-3-nitrotrifluoromethylbenzene (HC    Yellow No. 6),-   2,4-bis-[N-(2′-hydroxyethyl)amino]-5-chloronitrobenzene (HC Yellow    No. 10),-   4-(2′-hydroxyethyl)amino-3-nitromethylbenzene,-   4-(2′-hydroxyethyl)amino-3-nitrochlorobenzene (HC Yellow No. 12),-   4-(2′-hydroxyethyl)amino-3-nitrofluoromethylbenzene (HC Yellow No.    13),-   4-(2′-hydroxyethyl)amino-3-nitrobenzonitrile (HC Yellow No. 14),-   4-(2′-hydroxyethyl)amino-3-nitrobenzamide (HC Yellow No. 15).

As azo dyes can be mentioned, for example;

-   1-(4′-nitrophenylazo)-2-methylbis-(2′-hydroxyethyl)aminobenzene,-   1-(3′-nitro-4-amino)phenylazo-2-hydroxy-7-trimethylammoniumnaphthalene    chloride-   1-(2′-hydroxy-4′-sulfo-6′-nitro)naphthylazo-2-hydroxynaphthalene, CI    15,700-   1-(4′-aminophenylazo)-2-methyl-4-bis-[(2-hydroxyethyl)amino]benzene,-   5-(4′dimethylaminophenylazo)-1,4-dimethyltriazonium chloride,-   1-(2′-methoxyphenylazo)-2-hydroxy-7-trimethylammoniumnaphthalene    chloride,-   1-(4′-aminophenylazo)-2-hydroxy-7-trimethylammoniumnaphthalene,-   4-(3′-trimethylammoniumphenylazo)-N-phenyl-3-methyl-5-pyrazolone,-   4-hydroxy-3-[(4′-sulfo-1′-naphthyl)azo]-1-naphthalenesulfonic acid,-   1-(4′-sulfophenylazo)-2-hydroxynaphthalene,-   1-(4′-sulfophenylazo)-2-hydroxysulfonaphthalene, CI 15,985,-   4-amino-[4′-bis-(2″-hydroxyethyl)amino]azobenzene,-   4-amino[4′-bis-(2″-hydroxyethyl)amino]-2′-methylazobenzene,-   3-(2′,6′-diaminopyridyl-3′-azo)pyridine,-   7-phenylazo-1-amino-3,6-disulfo-8-hydroxynaphthalene,-   5-acetylamino-4-hydroxy-3-[(2′-methylphenyl)azo]-2,7-naphthalenedisulfonic    acid,-   2-(2′,4′-dimethylphenylazo)-6-(4″-sulfophenylazo)-1,3-dihydroxybenzene.

As quinone dyes can be mentioned, for example:

-   1,4-bis-(2′,3′-dihydroxypropyl)aminoanthraquinone,-   1-methylamino-4-(2′-hydroxyethyl)aminoanthraquinone-   2-(2′-aminoethyl)aminoanthraquinone,-   2-bromo-4,8-diamino-6-(3′-trimethylammonium)phenylamino-1,5-naphthoquinone,-   1-(2′-sulfo-4′-methylphenyl)amino-4-hydroxyanthraquinone,-   1,4-diaminoanthraquinone,-   1-amino-2-sulfo-4-cyclohexylaminoanthraquinone,-   1-aminopropylaminoanthraquinone,-   1,4-diamino-2-methoxyanthraquinone,-   1,4-bis-(2-hydroxyethyl)amino-5,8-dihydroxyanthraquinone.

As triphenylmethane dyes can be mentioned, for example:

-   4′,4″,4′″-triamino-3-methyltriphenylcarbonium chloride,-   bis-(4,4-diethylaminophenyl)-4′-ethylaminonaphthylcarbonium    chloride,-   bis-(4,4-dimethylaminophenyl)-4′-phenylaminonaphthylcarbonium    chloride, Basic Blue 26, CI 44,045, and-   4,4-bis-(N-ethyl-3-sulfobenzyl)amino-2″-sulfofuchsonium.

As acid dyes can be mentioned, for example:

-   1-(4′-sulfophenylazo)-2-hydroxy-6-sulfonaphthalene, CI 15,985,-   1-(2′-hydroxy-4′-sulfo-6′-nitro)naphthylazo-2-hydroxynaphthalene, CI    15,700,-   2,4-dinitro-1-naphthol-7-sulfonic acid disodium salt (Acid Yellow 1;    CI 10,316),-   2-(2′-quinolyl)-1H-indene-1,3(2H)-dione monodisulfonic acid disodium    salt (Acid Yellow 3; CI 47,005),-   4,5-dihydro-5-oxo-1-(4′-sulfophenyl)-4-[(4″-sulfophenyl)azo]-1H-pyrazole-3-carboxylic    acid trisodium salt (Acid Yellow 23; CI 19,140),-   3′,6′-dihydroxyspiro[isobenzofuran-1 (3H), 9′(9H)-xanthene]-3-one    (Acid Yellow 73; CI 45,350:1),-   5-[2′,4′-(dinitrophenyl)amino]-2-(phenylamino)benzenesulfonic acid    sodium salt (Acid Orange 3; CI 10,385),-   4-[(2′,4′-dihydroxyphenyl)azo]benzenesulfonic acid sodium salt (Acid    Orange 6; CI 14,270),-   4-[2′-hydroxy-1′-naphthyl)azo]benzenesulfonic acid sodium salt (Acid    Orange 7, CI 15,510-   4-[[3′-[(2″,4″-dimethylphenyl)azo]-2′,4′-dihydroxyphenyl]azo]benzenesulfonic    acid sodium salt (Acid Orange 24; CI 20,170),-   4-hydroxy-3-[(4′-sulfo-1′-naphthyl)azo]-1-naphthalenesulfonic acid    disodium salt (Acid Red 14; CI 14,720;-   7-hydroxy-8-[(4′-sulfo-1′-naphthyl)azo-1,3-naphthalenedisulfonic    acid trisodium salt (Acid Red 18; CI 16,285),-   3-hydroxy-4-[(4′-sulfo-1′-naphthyl)azo]-2,7-naphthalenedisulfonic    acid trisodium salt (Acid Red 27, CI 16,185);-   5-amino-4-hydroxy-3-phenylazo-2,7-naphthalene disulfonic acid    disodium salt (Acid Red 33, CI 17,200),-   5-(acetylamino)-4-hydroxy-3-[(2′-methylphenyl)azo]-2,7-naphthalenedisulfonic    acid disodium salt (Acid Red 35, CI 18,065),-   3′,6′dihydroxy-2′,4′,5′,7′-tetraiodospiro-fisobenzofuran-1(3H),    9′(9H)-xanthen]-3-one disodium salt (Acid Red 51, CI 45,430),-   3,6-bis-(diethylamino)-9-(2′,4′disulfophenyl)xanthylium hydroxide    sodium salt (Acid Red 52, CI 45,100).-   7-hydroxy-8-{[4′-phenylazo)phenyl]azo}-1,3-naphthalenedisulfonic    acid disodium salt (Acid Red 73, CI 27,290),-   2′,4′,5′,7′-tetrabromo-3′,6′dihydroxyspiro-[isobenzofuran-1 (3H),    9′(9H)-xanthen]-3-one disodium salt (Acid Red 87, CI 45,380),-   2′,4′,5′,7′-tetrabromo-4,5,6,7-tetrachloro-3′,6′dihydroxyspiro-[isobenzofuran-1(3H),    9′ (9H)-xanthen]-3-one disodium salt (Acid Red 92, CI 45,410),-   3′,6′-dihydroxy-4′,5′-diiodospiro-[isobenzofuran-1(3H),    9′(9H)-xanthen]-3-one disodium salt (Acid Red 95, CI 45,425), Acid    Red 195, Acid Blue 9 (CI 42,090),-   2,2′-[(9,10-dihydro-9,10-dioxo-1,4-anthracenediyl)diimino]-bis-(5-methylbenzenesulfonic    acid disodium salt (Acid Green 25, CI 61,570),-   N-{4-[(4′-dimethylamino)phenyl]-(2″-hydroxy-3″,6″-disulfo-1″-naphthyl)methylene}-2,5-cyclohexadien-1-ylidene-N-methylmethanaminium    hydroxide (Acid Green 50, CI 44,090),-   N-{4-[(4′-diethylamino)phenyl]-(2″,4″-disulfophenyl)methylene-2,5-cyclohexadien-1-ylidene}-N-ethylethanaminium    hydroxide sodium salt (Acid Blue 1, CI 42,045),-   N-{4-[(4′-diethylamino)phenyl]-(5″-hydroxy-2″,4″-disulfophenyl)methylene-2,5-cyclohexadien-1-ylidene}-N-ethylethanaminium    hydroxide calcium salt (Acid Blue 3, CI 42,051),-   1-amino-4-(cyclohexylamino)-9,10-dihydro-9,10-dioxo-2-anthracenesulfonic    acid sodium salt (Acid Blue 62, CI 62,045),-   2-(1′,3′-dihydro-3′-oxo-5′-sulfo-2′H-indol-2′-ylidene)-2,3-dihydro-3-oxo-1H-indole-5-sulfonic    acid disodium salt (Acid Blue 74, CI 73,015),-   9-(2′-carboxyphenyl)-3-[(2″-methylphenyl)amino]-6-[(2′″-methyl-4′″-sulfophenyl)amino]-xanthylium    hydroxide sodium salt (Acid Violet 9, CI 45,190),-   2-[(9′,10′-dihydro-4′-hydroxy-9′,10′-dioxo-1′-anthracenyl)amino]-5-methylbenzenesulfonic    acid sodium salt (Acid Violet 43, CI 60,730),-   3,3′-[sulfonyl-bis-(2-nitro-4′-phenylene)imino]-bis-[6-phenylamino)benzenesulfonic    acid disodium salt (Acid Brown 13, CI 10,410),-   4-amino-5-hydroxy-3-[(4′-nitrophenyl)azo]-6-(phenylazo)-2,7-naphthalenedisulfonic    acid disodium salt (Acid Black 1, CI 20,470),-   3-hydroxy-4-[(2′-hydroxy-1′-naphthyl)azo]-7-nitro-1-naphthalenesulfonic    acid sodium salt (Acid Black 52, CI 15,711),-   3-[(2,4-dimethyl-5-sulfophenyl)azo]-4-hydroxy-1-naphthalenesulfonic    acid (Ponceau SX, 0114,700).

As basic dyes can be mentioned, for example;

-   bis-4,4-dimethylaminophenyl)-4′-phenylaminonaphthylcarbonium    chloride (Basic Blue 26, CI 44,045),-   N    [[4′-(diethylamino)phenyl]-[4″-(ethylamino)-1″-naphthyl]methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanammonium    chloride (Basic Blue 7, CI 42,595),-   4-[(4′-aminophenyl)-(4′-imino-2′,5′cyclohexadien-1′-ylidene)methyl]-2-methylaminobenzene    hydrochloride (Basic Violet 14, CI 42,510),-   4-(acetylamino)-5-hydroxy-6-{[7′-sulfo-4-[(4″-sulfophenyl)azo]-1′-naphthyl]azo}-1,7-naphthalenedisulfonic    acid tetrasodium salt (Brilliant Black 1, CI 28,440),-   {[8-(p-aminophenyl)azo]-7-hydroxy-2-naphthyl}trimethylammonium    chloride (Basic Brown 16, CI 12,250),-   {8-[(4′-amino-2′-nitrophenyl)azo]-7-hydroxy-2-naphthyl}trimethylammonium    chloride (Basic Brown 17,12,251),-   7-hydroxy-8-[(2′-methoxyphenyl)azo]-N,N,N-trimethyl-2-naphthylammonium    chloride (Basic Red 76, CI 12,245),-   3-[(4′-amino-6′-bromo-5′,8′-dihydro-1′-hydroxy-8′-imino-5′-oxo-2′-naphthyl)amino]-N,N,N-trimethylammonium    chloride (Basic Blue 99, CI 56,059),-   4-(3′-trimethylammoniumphenylazo)-N-phenyl-3-methyl-5-pyrazolone    (Basic Yellow 57, CI 12,729).

The amounts of dyeing or coloring effector molecules, particularly hairdyes and preferably direct hair dyes, depend on the amounts known bythose skilled in the art to be used for dyeing hair. Said amounts canrange from a total of 0.001 to 10.0 wt. % and particularly from 0.001 to5.0 wt. %, based on the total amount of the cosmetic agent.

The first component, which can be referred to as the peptidic linkermolecule, comprises short-chain peptides that preferably are in the formof 2-mers to 30-mers, particularly 3-mers to 15-mers and moreparticularly 6-mers to 12-mers.

Preferred are peptides containing amino acid derivatives with a freeamino, hydroxy or sulfonyl group, for example the derivatives of3-aminoalanine, ornithine, lysine, serine, threonine, cysteine andhomocysteine. Suitable are, for example, the following peptides: AKKNRKTDND DS, DDDDE SEHHA KT, DDDE EEE, DDDEE EDQKR SKKHR, DDDEE HHHR, DDDEESEDES EEQ, DDEED EDPTK ARKT, DDEEE EEDE, DDEEE RRHKK, DDEES EE, DDERHHK, DDEHR K, DDETD DDSEP, DEDDE EETDN TSDNT, DEEDD EQKHK ATRT, DEEDEENKHH T, DEEDE TDDDE DNST, DEEEH HHH, DEETE DDKSR KQN, DEETK SHTSA DESS,DEKHH DKEE, DEKRT PQDTT LNQST, DETTQ TDKEE, EDDDS EPHHR SKQ, EDEED ENPTDES, EDDEE E, EEDDE EEE, EEDDE DDQHR NQ, EEDDP KKHH, EEDDS KRR, EEDEDEDPKQ HLLRN, EEDEE D, EEDEE SHHHK EEDSR RR, EEEDD EDDD, EEEDD NDQEE D,EEEDD TPEEE KEESK, EEEDE DD, EEEEE DSEDD, EEERK K, ESDED DDETQ PSTNT,ESEE EDPEE DE, HHKKH RTEED E, HHKRR KPESE EETS, HHKSR RRRHQ, HHRKE EE,HHRKK HRT, HHRKK K, HKKKE DDDD, HKRRH RRQKK QKS, HRKKR KKRPE EDDER,HTSDK EH, KHHRK RRDED TEEQ, KHHRK RRRK, KHSSS TTNEE EEQ, KKHDE DS, KKHDDE, KKHHT HTKRR N, KKKHR SKSDD DDQ, KKKKR EEDDE, KKKKR KKHKN NS, KKKNHSKHH KSS, KKKRR HS, KKRTT HHNEE EN, KRHHK RRHKD TDEEN, KRRHH R, KRRRH,KKKTK TSAK, KRTSN QPEDE RTHSL, NEDD DESNE EQ, NHHRD EHDEH S, RKKHE NDQ,RKKHR HREDE DEEDQ, RKKSE EEN, RRHHD DEE, RRKEE D, RRKKH HH, RRRHH HPEEDEDS, RRRHH KPRRA KH, RRRHH PRRK, RRTKK SHH, RTHHH DQEEE, SEETS SQTHHKATQ, SHEDD H, SHEHH TED, SHHKK KHHH KTKA, SHKKR KSRRH K, SSKKT QTRRN KS,SSKKT HQNST AT, SRRRK KHHSH, TDDDD EPSED T, TDDE DDEDD TDPN, TEEDS DPKKKQ, TEKHD EKDD, TGGGH KPEED S, THHES DK, THHRR EEED, TKEKD H, TTDENETTED, TSEES HSADE T, TSKHH RPTSS EKTS.

To the agent of the invention may be added other substances, auxiliaryagents and additives not attached to the peptidic linker, for examplethose commonly used for cosmetic products in general. Such materialsinclude, for example, thickeners (for example clays, starches,polyacrylic acid and the derivatives thereof, cellulose derivativeslanolin derivatives, vitamins or provitamins, (for example biotin,vitamin C, tocopherols or D-panthenol), antigrease agents, inorganic ororganic acids (for example lactic acid, citric acid, glycolic acid orphosphoric acid), preservatives (for example para-hydroxybenzoateesters), nonaqueous solvents, antioxidants (for example tocopherols orthe esters thereof), dyes and fragrances or perfumes, UV light-absorbinginorganic particles or pigments or micropigments, particularly metalcompounds or semimetallic compounds in ionic, nonionic or oxidized form.The pigments can be in this form either individually or in admixture oras individual mixed oxides or mixtures thereof, including mixtures ofmixed oxides and pure oxides. Examples are the titanium oxides (forexample TiO₂), zinc oxides (for example ZnO), aluminum oxides (forexample Al₂O₃), iron oxides (for example Fe₂O₃), manganese oxides (forexample MnO), silicon oxides (for example SiO₂), silicates, ceriumoxide, zirconium oxides (for example ZrO₂), barium sulfate (BaSO₄) ormixtures thereof. Suitable pigments or micropigments are commerciallyavailable. An example is Hombitec® L5 (INCI name: titanium dioxides)supplied by Merck.

Basically, those skilled in the art know which additives, auxiliaryagents and carriers are used in hair and skin cosmetics so that thefollowing statements are only of an exemplary nature and are intendedonly for further explanation of the present invention. Moreover, thereader is referred to the abundant literature describing the generalcomposition of cosmetic preparations and which is well known to thoseskilled in the art.

The additives, auxiliary agents and carriers can be used in the usualamounts known to those skilled in the art and can be incorporated bymethods in themselves known.

Before application, the first component, namely the peptidic linker, andthe second component, namely the effector molecule, are linked to eachother forming the high-affinity cosmetic agent of the invention, thefinished commercial product possibly containing other commonconstituents, auxiliary agents and carriers.

The cosmetic agents of the invention can be in the form of differentformulations known for cosmetic skin and hair products. For example,they can be in the form of shampoos, lotions, rinses, dispersions,emulsions, gels, cream gels, creams, lotions [sic], suspensions, sprays,aerosols or foams.

The present invention will now be explained in greater detail by meansof a dye as the effector molecule.

EXAMPLE 1 Preparation of5-((4-((5-amino-5-carboxypentyl)amino)-6-hydroxy-1,3,5-triazin-2-yl)amino)₄-hydroxy-3-(phenylazo)-2,7-naphthalenedisulfonicacid disodium salt (formula III)

Step 1

6.15 g (10 mmol) of Reactive Red 2 (based on 100% pure dye) and 2.0 g(11 mmol) of D,L-lysine hydrochloride were dissolved in 30 mL of water,and the pH was adjusted to 9-9.5 with 30% sodium hydroxide. The solutionwas then heated to 40° C. and stirred 6 hours while keeping the pH andtemperature constant. The mixture was cooled to room temperature, and5-((4-((5-amino-5-carboxypentyl)amino)-6-chloro-1,3,5-triazin-2-yl)amino)-4-hydroxy-3-(phenylazo)-2,7-naphthalenedisulfonicacid disodium salt was made to precipitate by addition of methanol in anamount commensurate with the crystallization.

Step 2

The moist product from Step 1 was taken up in 20 mL of water, 20 mL of30% sodium hydroxide solution was added, and the reaction mixture washeated to 90-C. After 6 hours, the mixture was cooled, carefullyacidified to pH 4.5 with acetic acid, and5-((4-((5-amino-5-carboxypentyl)amino)-6-hydroxy-1,3,5-triazin-2-yl)amino)-4-hydroxy-3-(phenylazo)-2,7-naphthalenedisulfonicacid disodium salt, (formula III) was made to precipitate by addition ofmethanol (about 40 mL). Filtering and drying gave 5.8 g of dye in theform of a red powder. The λ_(max) value of the dye in water was 544 nm.

EXAMPLE 2 Preparation of1-amino-4-((3-((2-(((5S)-5-amino-5-carboxypentyl)amino)ethyl)sulfonyl)phenyl)amino)-9,10-dioxo-9,10-dihydro-2-anthracenesulfonicacid sodium salt (formula V)

Step 1

6.26 g (10 mmol) of Reactive Blue 19 (based on 100% pure dye) and 2.7 g(11 mmol) of N(alpha)-BOC-L-lysine were dissolved in 30 mL of water, andthe pH was adjusted to 9-9.5 with 30% sodium hydroxide. The solution wasthen heated at 90° C. for 6 hours while keeping the pH constant at 4.5by addition of sodium hydroxide solution. The reaction product was thenmade to precipitate by addition of methanol (about 40 mL). Filtering anddrying gave 5.4 g (71% of the theoretical) of1-amino-4-((3-((2-(((5S)-5-(((1,1-dimethoxyethoxy)carbonyl)amino)-5-carboxypentyl)amino)ethyl)sulfonyl)phenyl)-amino-9,10-dioxo-9,10-dihydro-2-anthracenesulfonicacid sodium salt as a blue powder.

Step 2

2.0 g (2.6 mmol) of the compound from Step 1 was stirred in 10 mL ofhydrochloric acid (concentration: 1 mol/L) for 2 hours at roomtemperature. The dye was made to precipitate by addition of 20 mL ofmethanol. Filtering and drying gave 1.4 g (82% of the theoretical) of1-amino-4-((3-((2-(((5S)-5-amino-5-carboxypentyl)amino)ethyl)sulfonyl)phenyl)amino)-9,10-dioxo-9,10-dihydro-2-anthracenesulfonic acid sodiumsalt as a blue powder. The λ_(max) value of the dye in water was 598 nm.

EXAMPLE 3 Preparation of(2S)-2-amino-6-((2,4-dinitrophenyl)amino)hexanoic acid(N-6-(2,4-dinitrophenyl)-L-lysine)

Step 1

1.86 g (10 mmol) of 2,4-dinitrofluorobenzene and 2.7 g (10 mmol) ofN(alpha)-BOC-L-lysine were heated in 30 mL of acetonitrile at 90° C. for6 hours. The batch was cooled to room temperature, and the acetonitrilewas distilled off. This gave 4.1 g (99% of the theoretical) of6-((4-amino-2-nitrophenyl)amino-(2S)-2-(((1,1-dimethylmethoxy)carbonyl)amino)hexanoicacid (formula VI) as a bright yellow solid residue.

Step 2

3.2 g (7.8 mmol) of the compound from Step 1 was stirred in 10 mL ofhydrochloric acid in dioxane (concentration: 3 mol/L) at roomtemperature for 3 hours. At the end of the reaction, the dye was made toprecipitate by addition of 20 mL of diethyl ether. Filtering and dryinggave 2.1 g (95% of the theoretical) of(2S)-2-amino-6-((2,4-dinitrophenyl)amino)hexanoic acid(N-6-(2,4-dinitrophenyl)-L-lysine) (formula VII) as a bright-yellowpowder.

The lambda_(max) value of the dye in ethanol/water (1:1) was 412 nm.

SUMMARY

The present invention relates to a cosmetic agent consisting essentiallyof a peptidic linker and at least one cosmetic agent covalently linkedtherewith.

1. Cosmetic agent comprising two components with different functions andcovalently linked to each other, the first component being a peptidiclinker molecule with high affinity or binding specificity forkeratin-containing material, and the second component being at least onecosmetic agent consisting of at least one known organic cosmeticallyactive effector molecule.
 2. Cosmetic agent according to claim 1,characterized in that the said agent consists of at least onecosmetically active effector molecule or of several differentcosmetically active effector molecules.
 3. Cosmetic agent according toclaims 1 and 2, characterized in that the peptidic linker molecule has achain length between 2 and 30 amino acids.
 4. Cosmetic agent accordingto claims 1 to 3, characterized in that the cosmetically active effectormolecule has dyeing or coloring, cosmetic care-imparting, conditioning,protective, hardening softening, repairing and/or reconstitutingproperties.
 5. Cosmetic agent according to claim 4, characterized inthat the cosmetic effector molecule comprises at least one dye, hairconditioner, combability improver, polymer, surfactant, amidoamine,betaine ester, ester quat, silicon polyol, fatty alcohol, chitosan,humectant, vitamin, provitamin, vitamin precursor, springiness improver,betaine, sugar or UV filter.
 6. Cosmetic agent according to one ofclaims 1 to 5, characterized in that more than one cosmetic effectormolecule is linked with the peptidic linker and at least two differentcosmetic actions are exerted, or that said agent is provided withdifferent peptidic linkers having different binding strengths forkeratin-containing material and to which are attached different effectormolecules, or that said agent contains at least two different peptidiclinkers differing in terms of their binding strength and binding siteson the keratin-containing material.
 7. Use of a cosmetic agent accordingto claims 1 to 6 for the cosmetic treatment of keratin-containingmaterial in humans and animals.
 8. Use according to claim 7,characterized in that the keratin-containing material is animal or humanhair.
 9. Use according to claims 7 and 8, characterized in that thecosmetic agent contains as the effector molecule a dye and that it is ahair colorant.
 10. Use of a peptidic linker molecule and at least oneorganic cosmetically active effector molecule with dyeing or coloring,cosmetic care-imparting, conditioning, protective, hardening, softening,repairing and/or reconstituting properties for the preparation of acosmetic agent.
 11. Use according to claim 10, characterized in that thecosmetic agent is a hair-treatment agent.
 12. Use according to claims 10and 11, characterized in that the effector molecule is a dye and thatthe hair-treatment agent is a hair colorant.